Project Summary Breast cancer is genetically heterogeneous and there is substantial inter-individual variability in phenotypic expression of the disease. Several breast cancer subtypes have been proposed based on gene expression profiling and the utility of this approach has been demonstrated in predicting clinical outcomes. Genetic and environmental risk factors may also vary by molecular subtypes of breast cancer but there is limited data in this regard. Chromosome alterations, including loss of heterozygosity and copy number change, in tumor cells provide clues for identifying cancer related genes. Single nucleotide polymorphism (SNP) arrays have been used as an efficient approach to identifying chromosome alterations and their use in whole-genome association studies is increasing. Our long-term goal is to improve the prevention and treatment of breast cancer by identifying genetic variants predisposing to different subtypes of breast cancer. In this study, we propose an innovative approach to integrating gene expression profiling, SNP array-based chromosome alteration analysis, and association study. The specific aims are: (1) To determine the pattern of loss of heterozygosity and copy number alterations across breast cancer subtypes defined by gene expression;(2) to examine germline determinants of to breast cancer subtypes. This complementary approach will help narrow down novel candidate genes to small genomic regions and cross-validation of the findings from the two specific aims will effectively reduce false positive rate. Project narrative Breast cancer is the most common cancer among women and it is not widely accepted that breast cancer consists of several "subtypes" with different etiology and differential response to therapies. This study focuses on identifying the differences both in large chromosome changes and small genetic variations between tumors of breast cancer subtypes, in particular the basal-like subtype. We will interrogate these complementary data to pinpoint the genetic determinants of breast cancer development and progression, and, in turn, provide new knowledge for its prevention and treatment.